Abstract
Research has shown that HMGB1 can activate dendritic cells (DCs), but its molecular mechanisms are not clear. In this study, we reported that the myeloid dendritic cells (mDCs) were activated in the peripheral blood of SLE patients, and the activation of mDCs was associated with the up-regulation of HMGB1 and mTOR. After stimulated by HMGB1, expression of mTOR and its substrates P70S6K and 4EBP1 in dendritic cells increased considerably (P < 0.01). The expression of HLA-DR, CD40, and CD86 on dendritic cells also significantly increased following these stimuli (P < 0.01). In addition, stimulation with HMGB1 enhanced cytokine (IL-1β, IL-6, and TNF-a) production in dendritic cells. In contrast, the HMGB1-mediated expression of HLA-DR, CD40, and CD86 on dendritic cells and production of IL-1β, IL-6, and TNF-α were reduced by rapamycin. Rapamycin can inhibit HMGB1-induced activation of mDCs and secretion of pro-inflammatory cytokines. These findings indicated that HMGB1activates mDCs by up-regulating the mTOR pathway in SLE.
Highlights
Systemic lupus erythematosus (SLE) is a severe, debilitating autoimmune disease that affects multiple organs and body systems
Previous studies and our results revealed that the level of high-mobility group box protein-1 (HMGB1) was positively correlated with SLEDAI score in SLE patients, implying that the critical role of HMGB1 in the pathogenesis of SLE
We found that myeloid dendritic cells (mDCs) were activated in SLE
Summary
Systemic lupus erythematosus (SLE) is a severe, debilitating autoimmune disease that affects multiple organs and body systems. DCs can respond to encounter pathogens by producing inflammatory mediators, including proinflammatory cytokines [3]. Because of these complex roles, an imbalance in DC functions can cause a defective or exaggerated immune response and tissue damage. Research has shown that HMGB1, a non-histone nuclear protein, can induce immune responses and inflammatory responses that are relevant for the pathogenesis of SLE [4]. HMGB1 participates in the secretion of downstream proinflammatory cytokines via binding to cell surface receptors such as receptor of advanced glycation end products (RAGE), TLR2, and TLR4, contributing to the occurrence and development of diverse inflammatory diseases and autoimmune diseases [9,10,11,12,13,14]
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